Signal analysis biomarkers, in an intra-operative setting, may be complementary tools to guide and tailor the resection in drug-resistant focal epilepsy patients. Effective assessment of biomarker performances are needed to evaluate their clinical usefulness and translation. We defined a realistic ground-truth scenario and compared the effectiveness of different biomarkers alone and combined to localize epileptogenic tissue during surgery. We investigated the performances of univariate, bivariate and multivariate signal biomarkers applied to 1 min inter-ictal intra-operative electrocorticography to discriminate between epileptogenic and non-epileptogenic locations in 47 drug-resistant people with epilepsy (temporal and extra-temporal) who had been seizure-free one year after the operation. The best result using a single biomarker was obtained using the phase-amplitude coupling measure for which the epileptogenic tissue was localized in 17 out of 47 patients. Combining the whole set of biomarkers provided an improvement of the performances: 27 out of 47 patients. Repeating the analysis only on the temporal-lobe resections we detected the epileptogenic tissue in 29 out of 30 combining all the biomarkers. We suggest that the assessment of biomarker performances on a ground-truth scenario is required to have a proper estimate on how biomarkers translate into clinical use. Phase-amplitude coupling seems the best performing single biomarker and combining biomarkers improves localization of epileptogenic tissue. Performance achieved is not adequate as a tool in the operation theater yet, but it can improve the understanding of pathophysiological process.